The present invention concerns compounds useful as contrast media for angiography, formulations thereof, and methods of using the same. The present invention is particularly concerned with contrast media that have anticoagulant properties.
The occurrence of thrombosis during angiographic procedures is problematic. The anticoagulant properties of the currently available commercial contrast media are questionable. The nonionic contrast media are being investigated for their potential role in a thrombotic event during angiography. The ionic contrast media are thought to have some anticoagulant properties, however, they are less tolerated physiologically by the patient compared to nonionic contrast media. Accordingly, the provision of a contrast media with both anticoagulant properties and good physiological properties would be extremely valuable.
U.S. Pat. No. 3,953,501 to Klieger describes compounds of the formula: 
U.S. Pat. No. 4,264,572 to Klieger et al. describes X-Ray contrast media having the following general formula: 
P. Dawson, Embolic Problems in Angiography, Seminars in Hematology 28, 31-37 (1991), states that anticoagulant activity can not be provided in a non-ionic contrast agent without a general increase in toxicity of that agent.
The present invention provides basic ionic contrast agents that have anticoagulant activity.
A first aspect of the present invention is a compound of Formula I: 
wherein:
R1 is selected from the group consisting of alkyl and alkyl substituted with hydroxy or alkoxy;
R2, R3 and R4 are each independently selected from the group consisting of hydrogen and alkyl;
R5 and R6 are each independently selected from the group consisting of hydrogen, alkyl and hydroxyalky,
n is from 1 to 3;
Z isxe2x80x94Axe2x80x94NHCH3, or when R1 is hydroxy or alkoxy substituted alkyl and/or when R3 is loweralkyl, Z can also be hydroxy-C2-5-alkylamino;
A is: 
xe2x80x83wherein
R7 is H or alkyl;
R8 is H, alkyl, or alkyl substituted by hydroxy or alkoxy;
or together R7 and R8 form a propylene or hydroxypropylene ring;
m is 0 or 1;
R9 and R10 are each independently H or alkyl; or R9 and R10 together form C4-C8 (preferably C4) alkylene which is unsubstituted or substituted from one to three times with alkyl (e.g., methyl) or hydroxy;
R11 is amnino or guanidino;
o is from two to six, preferably 3 or 4; or a physiologically acceptable salt thereof.
A second aspect of the present invention is compounds Formula II: 
wherein:
R1 is selected from the group consisting of alkyl and alkyl substituted with hydroxy or alkoxy;
R2 is selected from the group consisting of hydrogen and alkyl;
R5 and R12 are each independently selected from the group consisting of hydrogen, alkyl and hydroxyalky,
R9 and R10 are each independently H or alkyl; or R9 and R10 together form C4-C8 (preferably C5) alkylene which is unsubstituted or substituted from one to three times with alkyl (e.g., methyl) or hydroxy;
R11 is amino or guanidino;
o is from two to six, preferably 3 or 4 or a physiologically acceptable salt thereof.
A third aspect of the present invention is a contrast media comprising an amount of a compound of Formula I or II above effective as a contrast medium in combination with a pharmaceutically acceptable carrier.
A fourth aspect of the present invention is the use of a compound of Formula I or II above for the preparation of a contrast media.
A fifth aspect of the present invention is a method of visualizing an internal organ or structure of a patient which comprises administering to the patient an amount of a compound of Formula I or II above effective as a contrast medium, and then exposing said organ or structure to a diagnostic imaging treatment. The structure to be imaged can be a platelet or fibrin thrombus.
The present invention is explained in greater detail in the specification set forth below.
Organs or structures that may be imaged by the contrast media of the present invention include blood vessels, a thrombus within a vessel, heart, brain, kidney, liver, lungs, spleen, etc. as well as portions thereof. Thus the entirety of an organ or structure need not be imaged, but only the portion thereof of diagnostic interest.
Diagnostic imaging treatments used to carry out the method of the present invention may be of any type, including magnetic resonance imaging and CT, but typically are X-ray diagnostic imaging treatments.
Alkyl as used herein is C1-4 loweralkyl; alkoxy as used herein is C1-C4 loweralkoxy, and more preferably C1-2 loweralkoxy.
The lower alkyl residue R1, which where appropriate can be substituted singly or multiply, may contain from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, in the alkyl residue. Suitable substituents include hydroxy, preferably 1-2 groups, or alkoxy of 1-2 carbon atoms, preferably one group. Preferred lower alkyl residues R1 have 1-2 carbon atoms and may be substituted by hydroxy or alkoxy, such as, e.g., methyl, ethyl, methoxymethyl, hydroxymethyl and the like.
Suitable lower alkyl residues for R2, R3 and R4 have 1-4 carbon atoms, preferably 1-2 carbon atoms, for instance methyl, ethyl, propyl, isopropyl and the like.
Suitable lower alkyl residues for R5 have 1-4 carbon atoms and especially have 1-2 carbon atoms, for instance, methyl or ethyl. This alkyl residue may optionally be substituted by hydroxy, preferably 1-2 groups; n preferably has a value of 1.
When Z is straight-chain or branched hydroxy lower alkylaiino, the alkyl residue may contain 2-5 carbon atoms, and, e.g., 1-3 hydroxy substituents. If Z is a straight chain group, the alkyl residue preferably contains 2-5 carbon atoms; if Z is branched, the alkyl residue preferably contains 3-5 carbon atoms. The hydroxy groups in Z may be present as primary or secondary hydroxy groups. Suitable Z residues include, e.g., 2-hydroxypropylamino, 3-hydroxypropylamino, 2-hydroxy-1, 1-dimethylethylamino, 3-hydroxy-1, 1-dimethylpropylamino and, preferably, 2-hydroxyethylamino.
Suitable bridging amino acid residues A include those derived from an amino carboxylic acid of arbitrary configuration. Included are those residues which are equivalents of, e.g., the preferred amino acid residue of the formula 
wherein m is 0 or 1, R7 is hydrogen or lower alkyl of 1-4 carbon atoms, preferably 1-2 carbon atoms, R8 is hydrogen or lower alkyl of 1-4 carbon atoms which also may be straightchain or branched and which may be substituted by hydroxy, preferably 1-2 groups or lower alkoxy of 1-2 carbon atoms, preferably 1-2 groups, and wherein R7 and R8 together may form a propylene or hydroxypropylene group. Examples of suitable aminocarboxylic acids include glycine, alanine, valine, serine, O-methylserine, proline, hydroxyproline, leucine, isoleucine, sarcosine, beta-alanine and the like. Especially preferred are alpha -amino-carboxylic acids in which R7 is hydrogen or methyl and R8 is hydrogen or lower alkyl of 1-2 carbon atoms which may be hydroxy- or methoxy-substituted.